The polyoma viruses (Polyomaviridae) are DNA viruses which infect a variety of species, including man. There are two polyoma viruses that cause disease in humans; BK virus (isolated from an immunosuppressed kidney transplant patient) and the human neurotropic polyomavirus JCV. Other polyoma viruses include the simian polyoma virus SV40, and the murine and avian polyoma viruses.
JCV is an established etiologic agent of progressive multifocal leukoencephalopathy, a fatal demyelinating disease of humans. Alwine J C (1982), J. Virol. 42, 798-803. Recent studies point to the association of JCV with several human cancers, including tumors of neural origin. See, e.g., Del Valle L et al., (2001a) Cancer Res 61: 4287-4293; Caldarelli-Stefano R et al., (2000) Human Pathol. 31: 394-395; and Khalili K et al. (1999), Lancet 353: 1152-1153.
As with other polyomaviruses, the genome of JCV is comprised of a double-stranded circular DNA that contains three functional regions. These functional regions are the early and late coding genomes, and the non-coding regulatory sequence. Frisque R J et al. (1984), J. Virol. 51: 458-469. The early genome is responsible for expression of the viral regulatory protein T-antigen. The late genome is expressed after DNA replication and results in the accumulation of the capsid proteins VP1, VP2, and VP3. In addition, the leader sequences of the late genome transcripts encompass an open reading frame encoding the agnoprotein.
During the 1980's, several laboratories studied polyomavirus agnoprotein. In particular the biological function of agnoprotein in SV40-infected monkey kidney cells was investigated. See, e.g., Alwine J C (1982) supra and Khalili K (1988), Proc. Natl Acad. Sci. USA 85: 354-358. These studies show that SV40 agnoprotein is important for the late events of the viral lytic cycle. In more recent studies, JCV agnoprotein was shown to interact with early T-antigen. See, e.g., Safak M et al. (2001), J. Virol. 75: 1476-1486. These studies suggest that T-antigen activity in viral gene transcription and DNA replication may be dictated, at least in part, by the interaction of T-antigen with agnoprotein. Thus, agnoprotein appears to have an integral function in polyoma viral replication.
As mentioned above, JCV infection has been linked to various tumors of central nervous system (CNS) origin, including medullablastoma, glioblastoma, and others. Del Valle L et al., (2001a), supra; Khalili K (1999), supra. Examination of T-antigen expression in the CNS tumor tissue revealed that not all tumor cells express T-antigen. Evaluation of these tumors for other viral proteins showed a substantial level of agnoprotein in tumors containing the JCV genome. DeValle L et al. (2002), J. Nat. Cancer Inst. 94(4): 267-273.
The importance of agnogene expression in brain tumor cells is unknown. One hypothesis holds that interactions of T-antigen and agnoprotein with each other, and with endogenous cellular proteins, may modulate the growth rate of tumor cells. Nevertheless, it appears from the studies discussed above that JCV agnoprotein is involved in the development and growth of some CNS neoplasms.